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Friday, October 12, 2007

INTRODUCTION — Hormone replacement therapy (HRT) refers to the use of hormones, including estrogen and progesterone, during and after the menopause. Estrogen levels fall at the time of menopause, producing well-known symptoms such as hot flashes and vaginal dryness. In addition, lower levels of estrogen are believed to increase a woman's risk for both bone thinning (osteoporosis) and heart disease after menopause. Many women use estrogen and progestin replacement to relieve bothersome symptoms of menopause.

This topic review provides information about the link between hormone replacement and breast cancer. Detailed discussions of the risks and benefits of HRT, available preparations, recommendations for who should or should not take estrogen, and alternatives to estrogen are found elsewhere. (See "Patient information: Postmenopausal hormone therapy" and see "Patient information: Alternatives to postmenopausal hormone therapy").

ESTROGEN AND BREAST CANCER — Estrogen is produced by the ovaries, although the amount of estrogen that is produced varies over a lifetime. Evidence from numerous studies indicate that exposure to naturally occurring estrogen can affect a woman's risk of breast cancer. The risk appears to increase with prolonged exposure (for women who have their first menstrual periods at an early age or menopause at a late age). The risk may also increase if she is exposed to high levels of estrogen. A full discussion of risk factors for breast cancer is available separately. (See "Patient information: Risk factors for breast cancer").

HRT AND BREAST CANCER — Estrogen and progesterone can stimulate breast cells to proliferate (grow and multiply). Proliferating cells are more likely to develop the genetic damage that leads to breast cancer. Furthermore, estrogen and progesterone can stimulate the growth of breast cancers that have already developed. Therefore, one of the main concerns for women thinking about taking HRT is the risk of developing breast cancer.

The best information about HRT and the risk of breast cancer is from the Women's Health Initiative (WHI), a large clinical trial comparing the risk of breast cancer in women who took HRT versus women who took a placebo (sugar pill). The WHI also examined the risk of other conditions, such as heart disease, bone thinning, and colon cancer. Women who did not have a uterus (eg, after hysterectomy) were randomly assigned to receive estrogen (Premarin) or placebo; women with a uterus received combined estrogen-progestin (Prempro) or placebo.

Estrogen plus progestin — Researchers expected to see a decreased risk of heart disease and a slightly increased risk of breast cancer in women who took hormones. Instead, they found that women who took combined estrogen-progestin had an increased risk of breast cancer and cardiovascular complications (heart attacks, strokes, blood clots). There were 38 cases of breast cancer per 10,000 women/year taking hormones versus 30 per 10,000 women taking placebo (sugar pills). This means that 8 additional women per year per 10,000 women developed breast cancer because of their use of estrogen-progestin. Similar findings have been noted in a number of other studies.

For these reasons, the estrogen plus progestin part of the trial was stopped in July 2002. Although there are other benefits of HRT (lower risk of osteoporotic fracture and colon cancer), the overall risks outweigh the benefits for many women if HRT is taken long-term. HRT is an effective short-term treatment for the relief of menopausal symptoms, but is no longer recommended long-term treatment (greater than five years).

One criticism of the WHI was that the average age of women who enrolled was 63 years. Thus, the results of the study may be different for peri- and newly postmenopausal women, who are typically 10 to 15 years younger. Therefore, the risks of HRT may be less concerning for women in their 50's compared to women in their 60's, especially if HRT is taken for less than five years.

Effects of progestins — There is good evidence that use of estrogen and a progestin increases the risk of breast cancer more than if estrogen is used alone. However, women who have a uterus should not take estrogen alone because of the increased risk of developing endometrial hyperplasia or uterine cancer; these conditions can develop after as little as six months of estrogen alone. Thus, women who have a uterus must take a progestin if estrogen is taken. For women who have had a hysterectomy, estrogen alone is preferred.

Estrogen alone — The results of the WHI trial of unopposed estrogen were different than those of combination estrogen and progestin: it showed an increased risk of stroke and blood clots, but no increase in breast cancer or heart attack risk. (See "Patient information: Postmenopausal hormone therapy").

Duration of use — All of these studies suggest that the major increase in breast cancer risk occurs after a woman has used estrogen-progestin for four to five years. Again, in the WHI, there was no increased risk of breast cancer in the women who took only estrogen.

Effects of past use — The risk of breast cancer associated with HRT decreases after a woman stops using HRT, even if she has taken HRT for a long time. In one study, the risk of breast cancer in women who had stopped using HRT more than five years ago was the same as the risk in women who had never been on HRT. Ongoing studies will help clarify the long-term effects of past HRT use on breast cancer risk.

Other factors that increase risk of breast cancer

Alcohol — Postmenopausal women on HRT who also drink alcohol (more than 1.5 to 2 drinks per day) appear to be at greater risk of breast cancer than HRT users who do not drink alcohol.

Family history of breast cancer — Some studies suggest that HRT further increases the risk of breast cancer in women who have a family history of this cancer. However, other studies have found that HRT does not increase the risk of breast cancer in women with a family history of breast cancer any more than in women without a family history of this cancer.

Personal history of breast cancer — Many women are now surviving for long periods of time after the diagnosis of a breast cancer because of earlier detection and improvements in treatment. As these women age, they are facing menopause (sometimes as a result of treatment-induced early menopause) and other health conditions such as osteoporosis.

The effects of HRT on the risk of a recurrence of breast cancer have been uncertain. However, in the HABITS trial, women with breast cancer who received HRT were at increased risk for a breast cancer recurrence.

Therefore, we do not recommend using estrogen or estrogen plus progestin in women with a personal history of breast cancer. Instead, alternatives to HRT should be tried. (See "Patient information: Alternatives to postmenopausal hormone therapy").

It was previously thought that women who developed breast cancer while taking HRT had a better chance of cure compared to women with breast cancer who were not taking HRT. Based upon the results of the WHI, this does not appear to be true.

SCREENING FOR BREAST CANCER — Regular breast cancer screening is essential for all women, especially those who decide to use HRT. Screening includes a combination of breast self-exams, annual breast exams with a healthcare provider, and an annual mammogram. (See "Patient information: Screening for breast cancer").

WHEN TO USE HORMONE REPLACEMENT THERAPY — Data from the Women's Health Initiative, as well as other trials, have led to changes in the recommendations for estrogen therapy [1,2]. Continuous estrogen-progestin therapy appears to increase the risks of cardiovascular events and breast cancer in women over age 60. Medications other than hormones are available to prevent and treat osteoporosis. As a result, long-term hormone replacement therapy to prevent heart disease or osteoporosis is not recommended. Most experts recommend avoiding hormone replacement therapy or using it for the shortest possible duration to control menopausal symptoms.

However, hormone replacement therapy is the most effective treatment for relief of menopausal symptoms. HRT is a reasonable option for most peri- or postmenopausal women, with the exception of those with a history of breast cancer, heart disease, a previous blood clot or stroke, or those at high risk for these complications. In otherwise healthy women, the risk of these complications is small.

In women being treated with HRT for symptoms, the goal is to eventually taper and stop the hormones (unless there is a compelling reason, such as quality of life, to continue it long-term). After the planned treatment interval, the hormones should be discontinued gradually, for example, by omitting one pill per week, to minimize recurrence of the menopausal symptoms.

After stopping HRT, there are several alternatives to HRT for treatment of menopausal symptoms and prevention of osteoporosis. (See "Patient information: Alternatives to postmenopausal hormone therapy").

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute

1-800-4-CANCER (www.nci.nih.gov)People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology (www.plwc.org/portal/site/PLWC)National Comprehensive Cancer Network